Many infectious diseases in humans are caused by virulent biofilms, including those occurring within the mouth (e.g., dental caries and periodontal diseases). For example, dental caries disease afflicts children and adults alike worldwide, and is a major reason for emergency room visits leading to absenteeism from work and school. The cost to treat the ravages of this disease exceeds $40 billion/yr in the US alone (Dye et al., 2007, Vital Health Stat, 1: 1-92).
The development of novel therapeutic approaches against biofilm-related diseases in the mouth is difficult due to (1) lack of retention of exogenously introduced agents via standard treatment regimen (topical application with brief exposures), (2) rapid clearance, and (3) the complexity of biofilm assembly. Topical agents must be retained or have prolonged effect without exhibiting broad-spectrum biocidal activity to prevent disruption of the complex oral (commensal) flora. At the same time, agents should not form complexes with salivary proteins that will lead to rapid clearance from the mouth.
The assembly of cariogenic biofilms is a dynamic process that is dependent on the development of a bacterial-derived EPS-rich matrix (Bowen et al., 2011, Caries Res, 45(1): 69-86). Within the complex oral microbiome, Streptococcus mutans is not always the most abundant organism. However, it can rapidly orchestrate the formation of cariogenic biofilms when sucrose becomes available. S. mutans-derived glucosyltransferases (Gtfs) are present in the pellicle and on bacterial surfaces, producing EPS in situ. EPS formed on surfaces promotes local accumulation of microbes on the teeth while forming a diffusion-limiting polymeric matrix that protects embedded bacteria. In parallel, sucrose and other sugars are fermented, creating acidic microenvironments (niches) across the biofilm and at the surface of attachment (Xiao et al., 2012, PLoS Pathog, 8(4): e1002623). These low-pH niches facilitate EPS production while cariogenic flora prospers within biofilms, ensuring biofilm accretion and localized acid-dissolution of the tooth enamel. Thus, nanoparticles can be engineered to carry existing and prospective agents at the site where biofilm formation actively occurs.
Current approaches for controlling/modulating virulent biofilm formation are limited. The development of novel therapeutic approaches in the mouth is difficult due to (1) lack of retention of exogenously introduced agents via standard treatment regimen (topical application with brief exposures), (2) rapid clearance from the mouth, and (3) the complexity of biofilm assembly. Topical agents must be retained or have prolonged effect without exhibiting broad-spectrum biocidal activity to prevent disruption of the complex oral (commensal) flora. Chlorhexidine is a broad-spectrum bactericidal agent that suppresses mutans streptococci levels in saliva, yet is far less effective against biofilms and is not suitable for daily preventive or therapeutic use. Fluoride, the mainstay for caries prevention, offers incomplete protection against caries and may not adequately address the infectious aspects of the disease (Ten Cate, 2012, J Dent Res, 91(9): 813-815). Recently, it has been demonstrated that that apigenin and farnesol effectively disrupt the development of cariogenic biofilm (Koo et al, 2005, J Dent Res, 84(11): 1016-1020; Falsetta et al., 2012, Antimicrob Agents Chemother, 56(12): 6201-6211). Apigenin inhibits EPS synthesis in situ while farnesol is a membrane-targeting agent that disrupts S. mutans acid tolerance at low pH values, all without bactericidal effect (Koo et al, 2005, J Dent Res, 84(11): 1016-1020). However, these agents have poor aqueous solubility and are not optimally retained in the mouth for sufficient duration to exert full therapeutic potential in vivo (Koo et al, 2005, J Dent Res, 84(11): 1016-1020).
Thus there is a need in the art for compositions and methods to provide effective retention of active agents while providing sustained and localized delivery of bioactives to the site where biofilm develops and accumulates. The present invention satisfies this unmet need.